Action Points

It is prudent to avoid coxibs in patients who have cardiovascular disease or are at risk for it.

An important and somewhat controversial current issue is whether or not the adverse effects of rofecoxib on the cardiovascular system are shared by all of the coxibs as a class. Even as Vioxx (rofecoxib) was approved in 1999, some studies were providing clues about the potential adverse effects of not just this one drug, but all coxibs on the cardiovascular system.

The author of several of those studies, Dr. Garrett A. FitzGerald, Professor of Cardiovascular Medicine, Professor of Pharmacology, and Chair of the Department of Pharmacology at the University of Pennsylvania believes he has pieced together those clues into a coherent picture. In the October 21 issue of the New England Journal of Medicine, he proposes a mechanism by which the entire class of coxibs predispose patients to myocardial infarction and thrombotic stroke, and he calls for updated FDA guidance on this issue.

Animal and human studies have shown that prostaglandin I2 is predominantly produced by the cyclooxygenase-2 (COX-2) enzyme while thromboxane A2 is produced by COX-1, FitzGerald notes.

Whereas aspirin and traditional NSAIDS inhibit both prostaglandin I2 and thromboxane A2, the coxib inhibitors, which target only the COX-2 enzyme, suppress only prostaglandin I2. This selective targeting allows the effects of thromboxane A2 to continue unchecked by I2, FitzGerald reasons.

"Thus, a single mechanism, depression of prostaglandin I2 formation, might be expected to elevate blood pressure, accelerate atherogenesis, and predispose patients receiving coxibs to an exaggerated thrombotic response to the rupture of an atherosclerotic plaque," FitzGerald argues. "The higher a patient's intrinsic risk of cardiovascular disease, the more likely it would be that such a hazard would manifest itself rapidly in the form of a clinical event."

While earlier trials for Vioxx (rofecoxib) and Celebrex (celecoxib) suggested some small cardiovascular risk, the evidence of gastrointestinal benefit appeared to outweigh that risk. "However, the APPROVe study has shifted the burden of proof," FitzGerald says. "We now have clear evidence of an increase in cardiovascular risk that revealed itself in a manner consistent with a mechanistic explanation that extends to all the coxibs."

Given this new information, the FDA should update its guidance on coxibs, FitzGerald says. In the absence of such guidance, FitzGerald offers some of his own. "Selective inhibitors of COX-2 remain a rational choice for patients at low cardiovascular risk who have serious gastrointestinal events, especially while taking traditional NSAIDs," he writes. "It would also seem prudent to avoid coxibs in patients who have cardiovascular disease or are at risk for it."

Reviewed by Zalman S. Agus, MD Emeritus Professor at the University of Pennsylvania School of Medicine